本文選題：發(fā)育性髖關節(jié)脫位 + 動物模型��； 參考：《復旦大學》2012年博士論文

【摘要】：[背景和目的] 發(fā)育性髖關節(jié)脫位(Developmental dislocation of the hip, DDH)是小兒矯形外科最常見的疾病之一,骨關節(jié)炎(Osteoarthritis, OA)是其最常見的遠期并發(fā)癥。與正常人相比,DDH骨關節(jié)炎發(fā)病年齡早且病情重,大多數(shù)必須進行全髖關節(jié)置換術(Total hip arthroplasty,THA),嚴重影響了生活質(zhì)量。本課題組前期研究發(fā)現(xiàn)發(fā)育性髖關節(jié)脫位早期可能已經(jīng)存在關節(jié)軟骨的退行性改變。目前對于DDH的早期發(fā)生關節(jié)軟骨退行性變及骨關節(jié)炎的分子生物學機制尚不明確,近年來有大量研究表明β-catenin及其所在Wnt信號通路在關節(jié)軟骨的形成和退行性改變中起關鍵作用,但β-catenin在髖關節(jié)脫位關節(jié)軟骨的早期退變中有無作用的研究尚未見報道。本研究旨在通過檢測β-catenin與關節(jié)軟骨早期退變有關的膠原、基質(zhì)金屬蛋白酶(MMPs)和解聚素等在DDH早期髖臼軟骨中的表達的相關性,探討β-catenin與DDH早期軟骨退行性變化的相關性,研究DDH早期軟骨退變的機制,為臨床DDH的早期預防骨關節(jié)炎提供理論依據(jù),為進一步深入研究DDH與骨性關節(jié)炎的關系提供新的思路。 [方法] 一、DDH動物模型的制作、病理組織學觀察 1.根據(jù)襁褓體位好發(fā)髖關節(jié)脫位,對新生20只Wistar大鼠雙下肢雙髖雙膝醫(yī)用膠帶并攏模擬襁褓體位固定10天,大體觀察證實制模成功情況。 2.實驗組大鼠固定10天后解除固定繼續(xù)飼養(yǎng),對2、4、6、8周DDH模型及對應周期正常發(fā)育大鼠各10只髖關節(jié)軟骨進行大體觀察,測量髖臼深度、長度及寬度；股骨頭長度及寬度。 3.髖關節(jié)軟骨標本Safranin O/Fast green染色后光鏡下觀察關節(jié)軟骨細胞與細胞外基質(zhì)的病理組織學改變。 二、X型膠原、基質(zhì)金屬蛋白酶-13(MMP-13)、ADAMTS-4、ADAMTS-5、β-catenin在不同時期DDH髖關節(jié)軟骨中的表達 1.第一部分DDH模型不同年齡和對應期對照鼠各10只髖關節(jié)軟骨標本。 2.采用免疫組化染色檢測X型膠原、MMP-13、β-catenin在不同年齡髖關節(jié)軟骨中表達的改變。 3.采用qRT-PCR法檢測X型膠原、MMP-13、ADAMTS-4、ADAMTS-5、β-catenin 在不同年齡髖關節(jié)軟骨中表達的改變,SPSS16.0統(tǒng)計和比較組間差異。三、體外軟骨細胞培養(yǎng),激活β-catenin的表達,檢測β-catenin對軟骨細胞 退行性改變的影響 1.8周對照組大鼠髖關節(jié)軟骨細胞的提取及原代培養(yǎng),Ⅱ型膠原免疫熒光及甲苯胺藍染色鑒定,免疫熒光及qRT-PCR檢測MMP13及X型膠原的表達,qRT-PCR檢測ADAMTS-5的表達,TUNEL法檢測軟骨細胞凋亡。 2.LiCl處理正常發(fā)育8周鼠關節(jié)軟骨細胞,激活β-catenin的表達,qRT-PCR檢測X型膠原、MMP-13和ADAMTS-5的表達；檢測軟骨細胞凋亡情況。 3. SPSS16.0統(tǒng)計和比較組間差異。 [結(jié)果] 一、DDH動物模型的制作及病理組織學觀察 1.建模成功率100%(20只新生大鼠固定10天)。 2.髖關節(jié)大體觀察：實驗組關節(jié)囊增厚,髖臼淺平,軟組織嵌入,股骨頭外形扁平,隨年齡增長頭臼匹配差距增大；測量結(jié)果顯示2、4周大鼠髖臼及股骨頭大小較對照組發(fā)育小,但仍呈發(fā)育增大趨勢,6周后髖臼發(fā)育基本停止,髖臼大小開始變小,股骨頭發(fā)育停止,頭臼不對稱進一步加重(P0.01)。 3. Safranin0/Fast green染色可見到實驗組關節(jié)軟骨退變征象：Safranin0染色淺層部分染色降低,表明帶負電荷蛋白多糖明顯降低、4周后關節(jié)軟骨淺層裂隙形成、淺層中層軟骨細胞簇聚及數(shù)量減少、關節(jié)軟骨退變隨鼠齡增長而加重。 二、X型膠原、基質(zhì)金屬蛋白酶-13(MMP-13)、ADAMTS-4、ADAMTS-5、B-catenin在不同時期DDH髖關節(jié)軟骨中的表達 1.實驗組X型膠原、MMP-13在軟骨層軟骨細胞中不均勻表達,成簇細胞表達明顯,胞漿內(nèi)明顯棕色深染細胞數(shù)目百分比較對照組多。4周及以后與對照組比較差異有統(tǒng)計學意義(P0.01),且隨鼠齡增長而表達增高。 2.實時熒光定量PCR結(jié)果顯示實驗組X型膠原和MMP-13mRNA在4周及以后表達較對照組增加,且隨鼠齡增長表達增加；ADAMTS-5在8周時表達增高,與對照組比較差異有統(tǒng)計學意義(P0.01)。ADAMTS-4與實驗組比較無統(tǒng)計學差異。 3. β-catenin:免疫組織化學中可見β-catenin在對照組大鼠2周時表達較多,隨鼠齡增長表達逐漸下降,8周時免疫組化基本無表達；實驗組β-catenin表達無下降趨勢,持續(xù)高表達；實時熒光定量PCR mRNA表達呈相似結(jié)果。 三、體外軟骨細胞培養(yǎng),檢測β-catenin對軟骨細胞退行性改變的影響 1.軟骨細胞培養(yǎng)及鑒定：軟骨細胞培養(yǎng)后Ⅱ型膠原免疫熒光及甲苯胺藍染色鑒定為軟骨細胞。 2. LiCl激活β-catenin表達：LiCl處理8周正常軟骨細胞后免疫熒光及qRT-PCR均提示β-catenin表達明顯增高。 3.激活β-catenin引起軟骨退行性改變：LiCl處理軟骨細胞免疫熒光提示X型膠原及MMP-13表達增高明顯；qRT-PCR提示X型膠原、MMP-13、ADAMTS-5表達增高(P0.01);TUNEL染色提示LiCl處理后軟骨細胞凋亡明顯增加(P0.01)。 [結(jié)論] 1.DDH動物模型早期關節(jié)軟骨發(fā)育落后并在4周出現(xiàn)發(fā)育停滯退變、軟骨蛋白多糖丟失等關節(jié)軟骨退變,這種早期發(fā)育異常及軟骨退變可能是DDH最終發(fā)生骨關節(jié)炎的病理學基礎。 2.與關節(jié)軟骨退變有關的X型膠原、MMP-13及ADAMTS-5在DDH早期就表達增多,可以作為反映DDH軟骨退變的早期敏感生物學指標。 3.β-catenin在正常發(fā)育早期有促進關節(jié)軟骨發(fā)育的作用,但成熟后不再表達,而在DDH整個發(fā)育過程中,關節(jié)軟骨出現(xiàn)持續(xù)高表達提示其可能是參與了軟骨退行性變。 4.關節(jié)軟骨發(fā)育異常導致β-catenin在DDH動物模型早期持續(xù)高表達,并可能引起X型膠原、MMP-13及ADAMTS-5等合成增多,軟骨細胞凋亡增加,由此導致關節(jié)軟骨早期退行性改變,這可能是DDH最終導致骨關節(jié)炎發(fā)生的機制之一
[Abstract]:[background and purpose]
Developmental dislocation of the hip (Developmental dislocation of the hip, DDH) is one of the most common diseases in pediatric orthopedics. Osteoarthritis (Osteoarthritis, OA) is the most common long-term complication. Compared with normal people, DDH osteoarthritis is early and is seriously ill, and most of them must be replaced by total hip arthroplasty (Total hip Arthr). Oplasty, THA), seriously affected the quality of life. Earlier studies in our group have found that there may have been degenerative changes in articular cartilage in the early stage of developmental dislocation of the hip. The molecular biological mechanism of osteoarthritis in the early stages of DDH is not clear. In recent years, a large number of studies have shown that beta -catenin and The Wnt signaling pathway plays a key role in the formation and degenerative changes of articular cartilage, but the study of the role of beta -catenin in the early degeneration of articular cartilage in the hip joint dislocation has not been reported. The aim of this study was to detect collagen, matrix metalloproteinase (MMPs) and depolymerization of beta -catenin and the early degeneration of articular cartilage. The correlation between the expression of element in the early acetabular cartilage of DDH and the correlation between the early chondrodegenerative changes of beta -catenin and DDH and the study of the mechanism of early cartilage degeneration in DDH provide a theoretical basis for the early prevention of osteoarthritis of the clinical DDH, and provide a new idea for further in-depth study of the relationship between DDH and osteoarthritis.
[method]
The production of DDH animal model, histopathological observation
1. according to the dislocation of the hip joint in the infancy, the new 20 Wistar rats with double hips and double knees and double knees and double knees were closed for 10 days, and the success of the model was confirmed by the general observation.
2. the rats in the experimental group were reared for 10 days after fixation. The 2,4,6,8 week DDH model and the 10 hip articular cartilage of the normal developing rats were observed, and the depth, length and width of the acetabulum were measured, and the length and width of the femoral head were measured.
3. histopathological changes of articular cartilage cells and extracellular matrix were observed by Safranin O/Fast green staining.
Two, the expression of type X collagen, matrix metalloproteinase -13 (MMP-13), ADAMTS-4, ADAMTS-5, and beta -catenin at different stages of DDH hip cartilage.
1. part I DDH model of 10 different age and corresponding control rats.
2. immunohistochemical staining was used to detect the expression of type X collagen, MMP-13 and beta -catenin in hip cartilage at different ages.
3. X collagen, MMP-13, ADAMTS-4, ADAMTS-5 and beta -catenin were detected by qRT-PCR.
Changes in cartilage expression in hip articular cartilage of different ages, SPSS16.0 statistics and comparison between groups. Three, in vitro chondrocyte culture, activation of the expression of beta -catenin, and detection of chondrocytes by beta -catenin
Effects of degenerative changes
The chondrocytes of the hip joint in the 1.8 week control group were extracted and cultured, the collagen type II was identified by immunofluorescence and toluidine blue, the expression of MMP13 and X collagen was detected by immunofluorescence and qRT-PCR, the expression of ADAMTS-5 was detected by qRT-PCR, and the apoptosis of cartilage cells was detected by TUNEL.
2.LiCl treated normal development of chondrocytes in 8 weeks and activated the expression of beta -catenin. QRT-PCR was used to detect the expression of X type collagen, MMP-13 and ADAMTS-5, and the apoptosis of cartilage cells was detected.
3. SPSS16.0 statistics and comparison between groups.
[results]
One, DDH animal model making and histopathological observation.
1. the success rate of modeling was 100% (20 newborn rats were fixed for 10 days).
2. hip joint gross observation: the joint capsule in the experimental group was thickened, the acetabulum was shallow, the soft tissue was embedded, the shape of the femoral head was flat, and the gap between the head of the head of the femoral head increased with age. The measurement results showed that the size of the acetabulum and the femoral head in 2,4 week rats was smaller than the control group, but the growth trend was still growing, the development of acetabulum was basically stopped after 6 weeks and the size of acetabulum began to begin. The development of femoral head was stopped and the asymmetry of the head and socket was further aggravated (P0.01).
3. Safranin0/Fast green staining showed the signs of articular cartilage degeneration in the experimental group: the superficial staining decreased in the superficial layer of Safranin0 staining, indicating that the negative charged protein polysaccharide was obviously reduced, the shallow fracture of the articular cartilage was formed after 4 weeks, the cartilage cells in the shallow layer were clustered and the number decreased, and the degeneration of articular cartilage was aggravated with the age of rat.
Two, the expression of type X collagen, matrix metalloproteinase -13 (MMP-13), ADAMTS-4, ADAMTS-5 and B-catenin in DDH hip cartilage at different stages.
1. the type X collagen in the experimental group was unevenly expressed in the chondrocytes of the chondrocytes, and the expression of the cluster cells was obvious. The number of brown deep stained cells in the cytoplasm was more than that of the control group for more than.4 weeks and after the control group, the difference was statistically significant (P0.01), and the expression increased with the growth of the rat age.
2. real time fluorescence quantitative PCR results showed that the expression of type X collagen and MMP-13mRNA in the experimental group was increased in 4 weeks and after the control group, and the expression increased with the age of rat. The expression of ADAMTS-5 increased at 8 weeks. There was a significant difference between the control group and the control group (P0.01).ADAMTS-4 and the experimental group.
3. beta -catenin: immunohistochemical staining showed that the expression of beta -catenin was more in the control group at 2 weeks, and gradually decreased with the growth of rat age. The expression of immuno histochemistry was basically no expression at 8 weeks, and the expression of beta -catenin in the experimental group had no downward trend and continued high expression, and the real-time fluorescence quantitative PCR mRNA table showed similar results.
Three, in vitro chondrocyte culture, to detect the effect of beta -catenin on the degeneration of chondrocytes.
1. chondrocyte culture and identification: chondrocytes cultured after type II collagen immunofluorescence and toluidine blue staining were identified as chondrocytes.
2. LiCl activated the expression of beta -catenin: immunofluorescence and qRT-PCR showed that the expression of beta -catenin increased significantly after LiCl treatment for 8 weeks in normal chondrocytes.
3. activation of beta -catenin induced degeneration of cartilage: LiCl treated chondrocyte immunofluorescence suggested that the expression of type X collagen and MMP-13 increased obviously; qRT-PCR suggested X collagen, MMP-13, ADAMTS-5 expression increased (P0.01); TUNEL staining suggested that apoptotic chondrocyte apoptosis was significantly increased after LiCl treatment (P0.01).
[Conclusion]
The early development of articular cartilage in the 1.DDH animal model is backward and the development of stagnation and degeneration, cartilage protein polysaccharide loss and other articular cartilage degeneration appear at 4 weeks. This early dysplasia and cartilage degeneration may be the pathological basis of osteoarthritis of DDH.
2. the expression of type X collagen, MMP-13 and ADAMTS-5 related to articular cartilage degeneration is increased in the early stage of DDH, which can be used as an early sensitive biological indicator to reflect the degeneration of DDH cartilage.
3. beta -catenin can promote articular cartilage development at the early stage of normal development, but no longer expression after maturation, and the continuous high expression of articular cartilage in the whole development of DDH suggests that it may be involved in degeneration of cartilage.
4. articular cartilage abnormal development leads to the high expression of beta -catenin in early DDH animal model, and may cause X collagen, MMP-13 and ADAMTS-5 synthesis increase, cartilage cell apoptosis increase, resulting in the early degeneration of articular cartilage, which may be one of the mechanisms that DDH eventually leads to the occurrence of osteoarthrosis.
【學位授予單位】：復旦大學
【學位級別】：博士
【學位授予年份】：2012
【分類號】：R726.8

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9 王超華;朱梅;張子博;劉軍;任凱晶;盧飚;李鳳翱;邱明才;;Wnt/β-catenin信號通路與骨關節(jié)炎發(fā)病機制的實驗研究[A];中華醫(yī)學會第十次全國內(nèi)分泌學學術會議論文匯編[C];2011年

10 劉志翔;張柳;張楠;;降鈣素對兔骨關節(jié)炎軟骨基質(zhì)金屬蛋白酶的影響[A];全國骨科臨床研究新進展研討會暨學習班論文集[C];2006年

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